دورية أكاديمية
VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system.
| العنوان: | VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system. |
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| المؤلفون: | So J; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Mabe NW; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, Massachusetts, USA., Englinger B; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, Massachusetts, USA.; Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Chow KH; Department of Oncologic Pathology and.; Center for Patient Derived Models, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Moyer SM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Yerrum S; Department of Oncologic Pathology and.; Center for Patient Derived Models, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Trissal MC; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, Massachusetts, USA., Marques JG; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, Massachusetts, USA., Kwon JJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Shim B; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Pal S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Panditharatna E; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, Massachusetts, USA., Quinn T; Department of Oncologic Pathology and.; Center for Patient Derived Models, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Schaefer DA; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, Massachusetts, USA., Jeong D; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, Massachusetts, USA., Mayhew DL; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Radiation Oncology, Tufts Medical Center, Boston, Massachusetts, USA., Hwang J; Department of Medicine and.; Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Beroukhim R; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Ligon KL; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; Department of Oncologic Pathology and., Stegmaier K; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, Massachusetts, USA., Filbin MG; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, Massachusetts, USA., Hahn WC; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. |
| المصدر: | JCI insight [JCI Insight] 2022 Oct 10; Vol. 7 (19). Date of Electronic Publication: 2022 Oct 10. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
| مواضيع طبية MeSH: | Glioma*/genetics , Neuroblastoma*/genetics , Vaccinia*, Child ; Humans ; Intracellular Signaling Peptides and Proteins ; Nervous System ; Protein Serine-Threonine Kinases/genetics ; Vaccinia virus |
| مستخلص: | Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout sensitized cells to VRK1 loss, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 loss. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced barrier-to-autointegration factor phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in VRK2 promoter-methylated adult and pediatric gliomas and neuroblastomas. |
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| معلومات مُعتمدة: | F32 CA261035 United States CA NCI NIH HHS; P01 CA217959 United States CA NCI NIH HHS; R35 CA210030 United States CA NCI NIH HHS; U01 CA176058 United States CA NCI NIH HHS; F32 CA243290 United States CA NCI NIH HHS; R03 TR003343 United States TR NCATS NIH HHS; K99 CA279915 United States CA NCI NIH HHS; R25 CA174650 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: Brain cancer; Cancer; Molecular genetics; Oncology |
| المشرفين على المادة: | 0 (Intracellular Signaling Peptides and Proteins) EC 2.7.11.1 (Protein Serine-Threonine Kinases) EC 2.7.11.1 (VRK1 protein, human) EC 2.7.11.1 (VRK2 protein, human) |
| تواريخ الأحداث: | Date Created: 20220830 Date Completed: 20221011 Latest Revision: 20240607 |
| رمز التحديث: | 20240607 |
| مُعرف محوري في PubMed: | PMC9675470 |
| DOI: | 10.1172/jci.insight.158755 |
| PMID: | 36040810 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2379-3708 |
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| DOI: | 10.1172/jci.insight.158755 |